ABSTRACT
Continued androgen receptor (AR) expression and signaling is a key driver in castration-resistant prostate cancer (CRPC) after classical androgen ablation therapies have failed, and therefore remains a target for the treatment of progressive disease. Here, we describe the biological characterization of AZD3514, an orally bioavailable drug that inhibits androgen-dependent and -independent AR signaling. AZD3514 modulates AR signaling through two distinct mechanisms, an inhibition of ligand-driven nuclear translocation of AR and a downregulation of receptor levels, both of which were observed in vitro and in vivo. AZD3514 inhibited testosterone-driven seminal vesicle development in juvenile male rats and the growth of androgen-dependent Dunning R3327H prostate tumors in adult rats. Furthermore, this class of compound showed antitumor activity in the HID28 mouse model of CRPC in vivo. AZD3514 is currently in phase I clinical evaluation.
Subject(s)
Androgen Receptor Antagonists/pharmacology , Antineoplastic Agents/pharmacology , Prostatic Neoplasms, Castration-Resistant/pathology , Pyridazines/pharmacology , Receptors, Androgen/metabolism , Seminal Vesicles/drug effects , Abiraterone Acetate , Androgen Receptor Antagonists/metabolism , Androstadienes/pharmacology , Animals , Antineoplastic Agents/metabolism , Benzamides , Cell Line, Tumor , Disease Models, Animal , Down-Regulation , Drug Screening Assays, Antitumor , Gene Expression Regulation, Neoplastic , HCT116 Cells , Humans , Male , Mice , Mice, Nude , Nitriles , Phenylthiohydantoin/analogs & derivatives , Phenylthiohydantoin/pharmacology , Prostatic Neoplasms, Castration-Resistant/drug therapy , Pyridazines/chemical synthesis , Pyridazines/metabolism , Rats , Rats, Wistar , Receptors, Androgen/genetics , Seminal Vesicles/growth & development , Signal Transduction/drug effects , Xenograft Model Antitumor AssaysABSTRACT
Removal of the basic piperazine nitrogen atom, introduction of a solubilising end group and partial reduction of the triazolopyridazine moiety in the previously-described lead androgen receptor downregulator 6-[4-(4-cyanobenzyl)piperazin-1-yl]-3-(trifluoromethyl)[1,2,4]triazolo[4,3-b]pyridazine (1) addressed hERG and physical property issues, and led to clinical candidate 6-(4-{4-[2-(4-acetylpiperazin-1-yl)ethoxy]phenyl}piperidin-1-yl)-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (12), designated AZD3514, that is being evaluated in a Phase I clinical trial in patients with castrate-resistant prostate cancer.
